Orphanet Journal of Rare Diseases | Novel ACADSB Variant Identified via Newborn Screening in Iran Leads to 2-MBDD

Recommend:

This study reports the first Iranian case of 2-MBDD and identifies a novel likely pathogenic variant, highlighting the critical role of newborn screening in early diagnosis of rare metabolic disorders.

 

Literature Overview

The article titled Identification of a novel ACADSB variant for the presymptomatic diagnosis of 2-Methylbutyryl-CoA dehydrogenase deficiency through newborn screening in Iran, published in Orphanet Journal of Rare Diseases, reviews and summarizes the screening, diagnosis, and treatment of the first reported case of 2-Methylbutyryl-CoA dehydrogenase deficiency (2-MBDD) in Iran. The study identified the disease through the national newborn screening program and, by genomic analysis, revealed a new ACADSB gene variant (c.907G > C; p.G303R), further emphasizing the importance of early intervention in disease management.

Background Knowledge

2-MBDD is a rare organic acidemia classified as a branched-chain amino acid metabolism disorder, primarily caused by mutations in the ACADSB gene that result in dysfunction of short/branched-chain acyl-CoA dehydrogenase (SBCAD). This defect affects isoleucine metabolism, leading to the accumulation of 2-methylbutyrylglycine (C5) in blood and urine. Most patients are asymptomatic in the neonatal period, but without early intervention, severe complications such as epilepsy, developmental delay, or cognitive impairments may develop later. Currently, there is limited global research on 2-MBDD, particularly a lack of gene variant data from the Middle East. Iran, a country with a high rate of consanguineous marriages and strong genetic heterogeneity, had not previously reported cases through its screening programs. Therefore, this study fills a critical gap in the literature. It not only provides an integrated workflow for metabolic screening and gene analysis but also highlights the necessity of expanding newborn screening programs and constructing an Iran-specific gene variant database to support precision medicine and genetic counseling.

 

Assesses the pathogenic potential of gene variants and provides a reference for analyzing variant function.

Learn More

 

Research Methods and Experiments

The study identified an asymptomatic male infant through Iran’s national newborn screening program. The screening used electrospray ionization-tandem mass spectrometry (ESI-MS/MS) to analyze dried blood spot (DBS) samples. Urine organic acid analysis was performed via gas chromatography-mass spectrometry (GC/MS), confirming the presence of 2-methylbutyrylglycine. Further clinical assessments included fundus examination, hearing tests, electroencephalography (EEG), echocardiography, and brain magnetic resonance imaging (MRI). Genomic DNA was extracted from peripheral blood and subjected to whole-exome sequencing (WES) using the Illumina HiSeq 4000 platform with an average sequencing depth of 150X. The Agilent SureSelectXT Human All Exon V6 kit was used for library preparation. Sequencing data were aligned to the GRCh37/hg19 reference genome, variant calling was performed using GATK, and annotation was conducted using ANNOVAR. Variants were filtered based on minor allele frequency (MAF) < 1% in population databases such as 1000 Genomes, ExAC, and gnomAD. Pathogenicity was assessed using the ACMG 2015 guidelines and predicted using multiple bioinformatics tools including MutationTaster, SIFT, PROVEAN, and CADD.

Key Findings and Insights

• First identification of a 2-MBDD case in Iran through newborn screening
• A novel missense variant in the ACADSB gene (c.907G > C; p.G303R) was identified, meeting ACMG criteria for likely pathogenicity
• The variant is located in a highly conserved domain, potentially affecting protein folding and catalytic function
• Early intervention with low-isoleucine diet and L-carnitine supplementation effectively prevented disease progression
• Combining metabolic screening with genetic sequencing is an effective strategy for diagnosing rare metabolic disorders
• The study suggests the necessity of larger-scale screening and establishing population-specific genetic databases in Iran

Significance and Future Directions

This study emphasizes the importance of expanding newborn screening programs in resource-limited regions. Integrating metabolomic and genomic analyses can significantly enhance early diagnosis rates of rare metabolic diseases. It also points out the underrepresentation of the Middle East in global genetic databases, making this study a valuable source of population-specific data. Future studies should include larger cohorts to validate the prevalence of the variant and conduct functional analyses to evaluate its biochemical impact. Establishing regional variant databases such as Iranome can improve diagnostic accuracy and the efficiency of genetic counseling.

 

Input a gene to view its associated signaling pathways and known upstream/downstream molecules.

Learn More

 

Conclusion

This study reports the first case of 2-MBDD in Iran and identifies a novel ACADSB gene variant (c.907G > C; p.G303R). Using newborn screening combined with genomic analysis, the research team successfully achieved presymptomatic diagnosis and effective clinical management through dietary intervention. The findings support the integration of metabolic screening and genetic testing into national screening programs, particularly in regions with high rates of consanguinity. Additionally, the discovery enriches the global 2-MBDD variant database, laying the foundation for future molecular studies and personalized therapeutic strategies. Further research should focus on the biochemical function and population distribution of this variant to better inform clinical applications and public health planning.

 

Maryam Nasri, Nejat Mahdieh, Farzaneh Abbasi, Reihaneh Mohsenipour, and Saeideh Abdolahpour. Identification of a novel ACADSB variant for the presymptomatic diagnosis of 2-Methylbutyryl-CoA dehydrogenase deficiency through newborn screening in Iran. Orphanet Journal of Rare Diseases.